All-trans Retinoic Acid For Induction Research Articles

Determinants of Fatal Bleeding during Induction Therapy for Acute Promyelocytic Leukemia in the ATRA Era

Background Acute promyelocytic leukemia (APL) is commonly complicated by complex coagulopathy. The early use of all-trans retinoic acid (ATRA) appears to have reduced induction mortality; however, with modern regimens the risk of early hemorrhagic death remains at about 5-10% in clinical trials and up to 30% in population-based studies. Previously identified as markers of bleeding risk in this setting are: white blood cell count (WBC), peripheral blood blast count, platelet count, fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT) and creatinine. Nonetheless, uncertainty remains as to which ones are independent predictors.Materials and Methods The database for study was from APL patients enrolled on three large clinical trials that used ATRA for induction: APML3 (single arm of ATRA + idarubicin ± prednisone), APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone) and ECOG 2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA). Known determinants of bleeding were assessed at baseline and considered as potential predictors of hemorrhagic death in the first 30 days of induction. In univariate analysis, using Wilcoxon Rank Sum and Fisher’s exact test, we looked at the association of the parameters mentioned above with hemorrhagic death within 30 days of induction.Results A total of 619 patients were enrolled: ECOG 2491 (intergroup I0129) - 394, APML3 - 101, and APML4 -124. Among these, thirty (4.8%) deaths from bleeding during the first 30 days (early deaths, ED) following induction were recorded. Baseline characteristics of the patients are shown in Table 1 and Table 2. Initial coagulation parameters (PT, aPTT and fibrinogen) were not available for the ECOG trial. Parameters with significant differences between the ED cases and the remaining of the cohort included WBC (median: 7.4 vs 2.4 /Kmcl respectively, p<0.001), peripheral blood blast count (median: 1.0 vs 0.2 /Kmcl respectively, p=0.049) and platelet count (median: 20 vs 33 /Kmcl respectively, p=0.002).Conclusions In this large cohort of approximately 600 APL patients enrolled on 3 large clinical trials, higher WBC, peripheral blast count and lower platelet count emerged as univariate predictors of early hemorrhagic death. Surprisingly, age, PT, aPTT, fibrinogen and creatinine clearance did not differ between the patients who died from bleeding and the remaining of the cohort. Multivariate analysis will clarify the relative strength of the significant predictors in assessing ED, and will be available, along with coagulation parameters for ECOG, at the time of presentation. These data hopefully will allow us to build a clinical prediction rule to identify patients at the highest risk of early hemorrhagic death. Such a stratification tool could prove useful in future trials testing novel approaches to treat the coagulopathy associated with APL.:Abstract 948. Table 1Baseline Characteristics of Patients, Continuous VariablesVariableTotalDeath from Bleeding within 30 daysNoYesNMedian(IQR)NMedian(IQR)NMedian(IQR)p-valueAge (years)61940.0(26.0 -54.0)58940.0(26.0 -54.0)3047.0(26.0 -63.0)0.15White Blood Cell Count (K/mcL)6112.5(1.2 -8.2)5822.4(1.1 -7.6)297.4(3.1 -20.7)<0.001Peripheral blood blast count (K/mcL)5810.2(0.0 -2.2)5520.2(0.0 -1.9)291.0(0.1 -5.7)0.049Hemoglobin (g/dL)6159.3(8.0 -10.5)5859.3(7.9 -10.5)309.4(8.2 -10.7)0.75Platelets (K/mcL)61531.0(17.0 -56.0)58533.0(17.0 -57.0)3020.0(13.0 -34.0)0.002Prothrombin time (s)18416.0(13.3 -18.2)17916.0(13.3 -18.1)516.7(16.5 -144.3)0.15Activated partial thromboplastin time (s)22529.0(26.0 -32.0)21629.0(26.0 -32.0)931.2(29.0 -38.0)0.07Fibrinogen (mg/dL)2171.8(1.3 -2.6)2081.8(1.3 -2.6)92.3(2.0 -2.5)0.36Creatinine Clearance (mg/dL)*225389(261.2 -511.6)216392(264.9 -512.4)9262(219.2 -432.0)0.15*calculated using the Jelliffe formula:Table 2Baseline Characteristics of Patients, Categorical Variables.VariableTotalDeath from Bleeding within 30 daysNoYesN%N%N%p-valueECOG Performance Status57993.5455293.722790.000.50Good(0-2)Poor(3-4)365.82335.60310.00Missing40.6540.6800FAB Classification24840.0623940.58930.00>0.95M3M3v6710.826511.0426.67Missing30449.1128548.391963.33 DisclosuresNo relevant conflicts of interest to declare.

Common Gene Expression Changes in Matched Pretreatment and Relapse Samples from Eastern Cooperative Oncology Group Acute Promyelocytic Leukemia (APL) Patients Treated on the Chemotherapy (C) or All-Trans Retinoic Acid (ATRA)-Containing (A) Randomization Arms of Protocol E2491.

This study was based on the hypothesis that a global comparison of gene expression levels between APL cells before treatment and at relapse might provide crucial information about molecular mechanisms involved in the selection of relapse clones. Matched samples were derived from 7 patients treated on protocol E2491 (randomization of newly diagnosed patients to either C alone or ATRA for induction and then to maintenance ATRA or observation after consolidation), 4 on A arms and 3 on the C arm. Comparable levels of promyeloblasts were present in the low-density mononuclear cell fraction derived from bone marrow (BM) or peripheral blood (PB) with 1 exception (Patient 4). [Display omitted] RNA was prepared by a guanidinium-cesium chloride gradient procedure, and gene expression analysis utilized the Affymetrix Human Genome U-133 Plus 2.0 chip. For unsupervised hierarchical cluster analysis, the normalized data were filtered by the following criteria: coefficient of variation across samples (standard deviation/mean) 〉0.7 and expression level ≥100 in at least 50% of samples. Although there was considerable heterogeneity, 1415 filtered genes clustered into three groups (UCG; see table): #1 with 6 pretreatment patients, #2 with 3 relapse patients (2 C and 1 A), and #3 with 1 pretreatment and 4 relapse patients (1 C and 3 A). Derivation of RNA from PB cells may have contributed to UCG #2 clustering. By supervised analysis, using the criteria of a mean difference of ≥100 between the pretreatment and relapse values and a p-value <.01 by paired t-tests, 443 genes were selected with a median false discovery rate of 13%. To further select a robust and consistent set of genes, an ad-hoc ‘leave-one paired sample-out' analysis was performed. 139 genes were selected across all 7 subsets and, for 116 genes, the difference between pretreatment and relapse values was ≥1.5-fold–40 upregulated (U) and 76 downregulated (D). The relapse changes in expression of named genes included those affecting signal transduction via ras-related genes (RASA1, D; RASSF1, U; RAB1B&5C, U; ARF6, U; RGS10, U) and protein kinase A (AKAP11, D; PRKAR1A, D), apoptosis (MAP3K5/ASK1, D; CFLAR/FLIP, D; FAF1, U; UBE2D2, U), chromatin (SMARCA2, D; SMARCB1, U; HNRPH3, D), cell division (ANAPC4, D; CDC2L6, D; CENPJ, D), interferon activity (IRF7, U), and microRNA synthesis (DICER1, D). Gene expression changes (>2.5-fold) in the 443 gene set included: HGF, 3.6xD; APAF1, 3.4xD; IRF1, 2.6xU; FOSL1, 2.7xU; TGFB1, 2.9xU; RELB, 3.7xU; MAFF, 4.3xU. Although highly diverse, these findings point to potentially drug-targetable alterations of AP-1 and NFΚB transcriptional control in association with alterations in ras- and PKA-regulated signal transduction pathways and possibly to microRNA synthesis as common molecular processes in APL cells related to disease progression and relapse.

Aberrant promoter methylation of the retinoic acid receptor alpha gene in acute promyelocytic leukemia

The retinoic acid receptor alpha (RARA) gene is disrupted by PML/RARA fusion in acute promyelocytic leukemia (APL). The P2 promoter of RARA, controlling the RARalpha2 isoform, contains an RA-responsive element and may be targeted in APL. To test whether aberrant methylation of P2 was involved, 47 APL at diagnosis, 16 APL at first relapse, 50 acute myeloid leukemia (AML) and 22 acute lymphoblastic leukemia (ALL) were tested by methylation-specific polymerase chain reaction. RARA P2 methylation was highly associated with APL (APL: 25/63 vs AML/ALL: 2/75, P<0.0001). P2 methylation occurred at similar frequencies in APL at diagnosis and relapse, suggesting it was an initiating leukemogenic event. In the APL line NB4, RARalpha2 was not expressed, with the untranslocated RARA shown to be P2 methylated. 5-Azacytadine treatment of NB4 led to progressive P2 demethylation and re-expression of RARalpha2, confirming that RARA methylation collaborated with PML/RARA in totally suppressing RARalpha. In APL, RARA P2 methylation was unrelated to gender, age, presenting leukocyte counts and additional cytogenetic aberrations. For APL patients receiving all-trans retinoic acid for induction, P2 methylation did not affect the complete remission rates and survivals. RARA is the first myeloid-specific transcription factor shown to be dysregulated by both translocation and aberrant methylation.

The clinical features of 202 cases with acute promyelocytic leukemia and the analysis of related elements

目的 总结全反式维甲酸(ATRA)治疗急性早幼粒细胞白血病(APL)临床资料,探讨影响其长期生存的相关因素.方法采用临床病例分析方法.ATRA诱导缓解治疗急性早幼粒细胞白血病202例.缓解后按所接受的维持治疗分为维甲酸加化疗序贯交替组53例,单用化疗组50例,终止治疗组21例.观察长期生存率与年龄、性别、初诊时血液学指标的关系.结果202例患者中20例在接受ATRA治疗2周内死亡,早期病死率9.9%.182例患者中166例获得完全缓解(CR),缓解率91.2%.3年生存率40.4%,5年以上生存率22.6%(28/124).APL合并中枢神经系统(CNS)浸润发生率为7.4%(15/202).长期生存患者年龄在35岁以下者占85.7%.复发61例,复发率49.2%.结论年龄、初诊时白细胞数、白血病细胞浸润程度和合并CNS浸润是影响APL患者长期生存的重要因素.PML/RARα融合基因持续阳性或由阴性转为阳性常与复发有关,而持续阴性常伴随长期无病生存。

Pulmonary Embolism and Thrombotic Thrombocytopenic Purpura in Acute Promyelocytic Leukemia Treated with All-trans Retinoic Acid

We describe a patient with acute promyelocytic leukemia (APL) who developed pulmonary embolism (PE) and thrombotic thrombocytopenic purpura (TTP) during remission induction all-trans retinoic acid (ATRA) therapy. A 44-year-old man was diagnosed with APL and was treated with ATRA. On day 14, he developed PE, and on day 24, he developed TTP. Both PE and TTP occurred in association with leukocytosis due to ATRA administration. The PE responded to dexamethasone and TTP responded to plasma infusion. The PE and TTP remitted, and he achieved complete remission of APL. To our knowledge, there have been no reports of TTP occurring as a complication of ATRA therapy.

All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol: Presented in part at the 39th meeting of the American Society of Hematology, New Orleans, LA, December 1999.

We previously reported a benefit for all-trans retinoic acid (ATRA) in both induction and maintenance therapy in patients with acute promyelocytic leukemia (APL). To determine the durability of this benefit and identify important prognostic factors, long-term follow-up of the North American Intergroup APL trial is reported. A total of 350 patients with newly diagnosed APL were randomized to either daunorubicin and cytarabine (DA) or ATRA for induction and then either ATRA maintenance or observation following consolidation chemotherapy. The complete remission (CR) rates were not significantly different between the ATRA and DA groups (70% and 73%, respectively). However, the 5-year disease-free survival (DFS) and overall survival (OS) were longer with ATRA than with DA for induction (69% vs 29% and 69% vs 45%, respectively). Based on both induction and maintenance randomizations, the 5-year DFS was 16% for patients randomized to DA and observation, 47% for DA and ATRA, 55% for ATRA and observation, and 74% for ATRA and ATRA. There was no advantage of either induction regimen among any subgroups when CR alone was considered. However, female sex, classical M3 morphology (vs the microgranular variant [M3v]), and treatment-white blood cell count (WBC) interaction (ATRA/WBC below 2 x 10(9)/L [2000/microL] best, DA/WBC above 2 x 10(9)/L worst) were each significantly associated with improved DFS (P <.05). Treatment with ATRA, WBC below 2 x 10(9)/L, and absence of bleeding disorder were each significantly associated with improved OS. Age more than 15 years, female sex, and treatment-morphology interaction (DA/M3v worst, ATRA best regardless of morphology) were each significantly associated with improved DFS based on maintenance randomization. The improvement in outcome with ATRA in APL was maintained with long-term follow-up.

Determination of the optimal time and dosage of all-trans retinoic acid for induction of murine exencephaly.

Murine exencephaly corresponds to human anencephaly, and provides a model for studying the mechanism of development of the central nervous system. A system which induces exencephaly at an extremely high rate is required in order to examine embryos, before the stage of neural tube closure, as samples of future exencephaly. Herein, we report on a system which is close enough to the best conditions for induction of this malformation, involving ICR mice and all-trans retinoic acid. The intraperitoneal administration of 30 mg/kg of all-trans retinoic acid at 03:00 hr on day 8 (copulatory plug, day 0) induced exencephaly in 81.6% of live embryos, as evaluated on day 10, with a 41.7% embryonic death rate. Earlier administration (more than 3 hr before) greatly increased the rate of embryonic death, whereas later administration resulted in a reduction in the rate of exencephaly. These findings suggest that a specific time during early development is crucial for neural tube closure, and provide a system which may facilitate the study of neural development and the pathophysiology of human anencephaly.